Alzheimer's disease (AD) is a progressive, degenerative disease of the brain. Alzheimer's disease is one of several disorders that cause the gradual loss of brain cells. German physician Dr. Alois Alzheimer first described the disease in 1906. Although the disease was once considered rare, research has shown that it is the leading cause of dementia.
Dementia is an umbrella term for several symptoms related to a decline in thinking skills. Common symptoms include a gradual loss of memory, problems with reasoning or judgment, disorientation, difficulty in learning, loss of language skills, and decline in the ability to perform routine tasks. People with dementia also experience changes in their personalities and behavioral problems, such as agitation, anxiety, delusions (believing in a reality that does not exist), and hallucinations (seeing things that do not exist).
Several disorders that are similar to Alzheimer's disease can cause dementia. These include fronto-temporal dementia, dementia with Lewy bodies, Parkinson's disease, Creutzfeldt-Jakob disease, and Huntington's disease. All of these disorders involve disease processes that destroy brain cells.
Vascular dementia is a disorder caused by the disruption of blood flow to the brain. This may be the result of a massive stroke or several tiny strokes. Some treatable conditions—such as depression, drug interactions, and thyroid problems—can cause dementia. If treated early enough, this dementia may be effectively treated and even reversed.
According to the Alzheimer's Association website, Oct. 31, 2002 (http://www.alz.org):
Approximately 4 million Americans have AD. In a 1993 national survey, 19 million Americans said they had a family member with AD, and 37 million said they knew someone with AD;
14 million Americans will have AD by the middle of this century (2050) unless a cure or prevention is found;
One in 10 persons over 65 and nearly half of those over 85 have AD;
A small percentage of people as young as their 30's and 40's get the disease;
A person with AD will live an average of eight years and as many as 20 years or more from the onset of symptoms;
U.S. society spends at least $100 billion a year on treatment and care of persons with AD;
Neither Medicare nor most private health insurance covers the long-term care most patients need. Alzheimer's disease is costing American business $61 billion a year—$36.5 billion is the cost to business of caregiving (lost productivity from absenteeism of employees who care for family members with Alzheimer's); the rest is the business share of the costs of health and long-term care;
More than 7 of 10 people with Alzheimer's disease live at home. Almost 75% of the home care is provided by family and friends. The remainder is “paid” care costing an average of $12,500 per year. Families pay almost all of that out-of-pocket;
Half of all nursing home residents suffer from AD or a related disorder. The average cost for nursing home care is $42,000 per year but can exceed $70,000 per year in some areas of the country. The average lifetime cost per patient is $174,000; and
The Alzheimer's Association has granted nearly $120 million dollars in research grants (since 1982). The federal government estimates spending approximately $598.9 million for Alzheimer disease research in FY2002.
Alzheimer's disease advances at widely different rates. The duration of the illness can vary from 3 to 20 years. The areas of the brain that control memory and thinking skills are affected first, but as the disease progresses, cells die in other regions of the brain. Eventually, the person with Alzheimer's will need complete care. If the individual has no other serious illness, the loss of brain function itself will cause death.
No one knows yet exactly what causes Alzheimer's disease. Researchers are learning about what happens to the brain as we grow older, what happens to brain cells in Alzheimer's disease, genes associated with Alzheimer's, and many other factors that may be important. Most researchers agree that the cause may be a complex set of factors.
Studies have shown that the greatest known risk for developing Alzheimer's is increasing age. As many as 10 percent of all people 65 years of age and older have Alzheimer's. As many as 50 percent of all people 85 and older have the disease. A family history of the disease is another known risk. Having a parent or sibling with the disease increases an individual's chances of developing Alzheimer's.
There is no cure for Alzheimer's disease. However, there are several drug treatments that may improve or stabilize symptoms and several care strategies and activities that may minimize or prevent behavioral problems. Researchers continue to look for new treatments to alter the course of the disease and other strategies to improve the quality of life for people with dementia.
Mild cognitive impairment (MCI), operationally defined as isolated episodic memory decline, has recently emerged as the clinical entity that most conveniently and reliably represents incipient Alzheimer's disease (AD). Arch. Neurol., 58:1985 (2001). The risk of conversion to AD is higher in MCI than in the general aged population, as up to 50% of these patients develop the disease within two years. Neurology, 41:1006 (1991). Additionally, MCI is associated with an increased risk of developing dementia: patients develop dementia at a rate of 10-15% per year compared with healthy controls who develop dementia at a rate of 1-2% per year. Acta. Psychiatr. Scand., 106:403 (2002).
Glutamate is one neurotransmitter implicated in Alzheimer's disease. Glutamate is the principal excitatory amino acid neurotransmitter in cortical and hippocampal neurons. Neurology, 46:661-65 (1996). Accumulating evidence suggests that the cortical neuronal loss underlying dementia may be related to an increased sensitivity to glutamate and/or sustained elevations of glutamate levels. Int. J. Geriatr. Psychiatry, 14:3 (1999). This leads to a cumulative influx of calcium into neurons, impaired neuronal homeostasis, and eventually neurodegeneration, resulting in cell death. Biol. Psychiatry, 41:135 (1997); Prog. Brain. Res., 116:331 (1998); and Neurobiol. Aging, 10:593 (1989). One of the receptors activated by glutamate is the N-methyl-D-aspartate (NMDA) receptor, which is involved physiologically in learning and memory. Pharmacol. Review, 50:597 (1998). Because excessive NMDA receptor stimulation induced by ischemia leads to excitotoxicity (Prog. Brain Res., 116:331 (1998)), agents that block pathological stimulation of NMDA receptors might be anticipated to protect against further cortical neurodegeneration in dementia while the physiological function of the remaining neurons could be restored, resulting in symptomatic improvement. J. Neural. Trans. Suppl., 43:91 (1994).
Noradrenaline, also known as norepinephrine (NE) is another key neurotransmitter that may be involved in Alzheimer's disease. Disruption of normal noradrenergic (NA) functions has been implicated in the pathophysiology of both schizophrenia and AD. Biol. Psychiatry, 46:1243 (1999).
The locus ceruleus (LC) is the main subcortical site of norepinephrine (NE) synthesis and its precursor enzymes. Noradrenergic axons arising from the LC neurons project to several cortical areas, including the hippocampus, entorhinal cortex, and frontal cortex, where their axon terminals are in close contact with neurons, astrocytes, and brain microvessels. Neurosci. Lett., 97:203 (1989) and Brain Res. Bull., 45:247 (1998). The LC-generated NE plays an important role in selective attention, general arousal, and stress reactions in response to challenging environmental situations. Physiol. Rev., 63:844 (1983) and Brain Res., 531:189 (1990).
Two distinct cellular projections are involved in the central noradrenergic system: those originating from the ventrolateral tegmental noradrenergic cells, which are associated mainly with sexual and feeding behaviors; and those originating from the locus ceruleus (LC) cells, which are associated with certain cognitive functions (Crow, Nature, 219:736 (1968); Mason and Iversen, Brain Res. Rev., 1:107 (1979)). Furthermore, the prefrontal cortex (PFC) is rich in noradrenergic terminal fields from the LC, where it is believed that norepinephrine (NE) acts to reduce distractibility by strengthening PFC function. It is also believed that the PFC contributes to the cognitive dysfunction seen in a variety of neuropsychiatric disorders (e.g., attention deficit hyperactivity disorder (ADHD), Korsakoff's syndrome, and schizophrenia; Arnsten et al., Arch. Gen. Psychiatry, 53:448 (1996)). Therefore, dysfunction of noradrenergic receptors in the PFC could contribute to the pathophysiology of cognitive dysfunction associated with these conditions.
Cognitive deficits, similar to those seen in the neuropsychiatric disorders just mentioned, can be produced in animals by producing lesions of the LC noradrenergic system. These include deficits in sustained attention (Carli et al., Behav. Brain Res., 9:361 (1983); Cole and Robbins, Neuropsychopharmacology, 7:129 (1992)) and shifting attention (Devauges and Sara, Behav. Brain Research, 39:19 (1990)). In addition, rats with lesions of the LC demonstrate impaired learning directly associated with decreased levels of cortical NE (Anlezark et al., Science, 181:682 (1973)). These deficits are reversible with the administration of drugs that enhance noradrenergic neurotransmission. For example, the administration of diethyldithiocarbamate (DDC), an inhibitor of the enzyme dopamine-beta-hydroxylase (DBH), to rats depletes NE stores in the brain, and produces complete retention failure of passive avoidance learning (Hamburg and Cohen, Pharmacol. Biochem. Behav., 1:295 (1973); Stein et al., Brain Res., 84:329(1975)). Subsequently, normal learning of the passive avoidance task is restored in DDC-treated rats with a single intraventricular dose of NE (Stein et al., Brain Res., 84:329 (1975)). In addition, puromycin-induced amnesia for maze learning in rats is reversed by the administration of drugs increasing noradrenergic activity, such as imipramine, tranylcypromine, and D-amphetamine (Roberts et al., Proc. Natl. Acad. Sci. USA, 66:310 (1970)).
However, drugs that nonspecifically increase noradrenergic activity, such as tricyclic antidepressants, monoamine oxidase inhibitors, amphetamines, and specific norepinephrine reuptake inhibitors, may be detrimental to cognition in neuropsychiatric conditions where PFC functions are compromised.
Experimentally induced loss of LC neurons (which, again, are involved in the noradrenergic system) has been implicated in learning and behavior deficits. Science, 181:682 (1973); Nature, 285:422 (1975); and J. Neurol. Transcm., 106:619 (1999). Loss of LC neurons, degeneration of noradrenergic (NA) projections, and a decrease in cortical NE levels are well-described features of various neurodegenerative diseases, including AD and Parkinson's disease. Journal of Neuroscience, 22(7):2434 (2002). In addition, decreased LC neuronal counts are significantly correlated with the severity of dementia in AD.
Thus, two classic pathological hallmarks of AD are LC loss and decreased noradrenergic (NA) innervation. Recent evidence suggests a link between these two. Neurobiol. Aging, 21:383 (2000). It has been hypothesized that neuronal LC loss and neuropathological and inflammatory changes are members of a vicious self-maintaining and self-stimulating cycle, with no guidance at which point and by what treatment a beneficial interruption of this cycle can be achieved. Neurobiol. Aging, 21:383 (2000).
Another neurotransmitter that may be involved in Alzheimer's disease is serotonin. Over the last decades, extensive evidence has suggested that serotonin and the serotonergic system plays an important modulatory role in learning and memory through action on specific receptors and interaction with multiple neurotransmitter systems, such as glutamatergic, cholinergic, dopaminergic or GABAergic pathways. Annals of Medicine, 32:210 (2000). Because of their distribution in the limbic areas and in the frontal cortex (Neuropharmacology, 33:527 (1994)), serotonin receptors are proposed to be involved in cognitive processes. British Journal of Pharmacology 115, 1387-1392 (1995) and Neuropharmacology, 38:1083 (1999). Neurochemical, electrophysiological and behavioral studies support a role for those receptors in cholinergically-mediated memory process.
Serotoninergic and cholinergic manipulations are known to influence cognition. Neuroscience, 69:1 (1995) and European Journal of Neuroscience, 12:67 (2000). Post-mortem studies revealed that the hippocampal serotonin receptor density declines in patients with cholinergic and memory alterations such as those observed in AD. Behavior and Brain Research 73:249 (1996). Overall, results of the literature suggest that serotonin receptor agonists may improve the rate of learning; however, most of the available arguments have been obtained under pre-induced, altered, conditions and almost no information is available in normal conditions. Neuropharmacology. 41:517 (2001).
Patients with Alzheimer dementia frequently have severe reductions in brain cholinergic and serotonergic function (Semin. Neurosci. 2:101 (1990)), suggesting that simultaneous reduction of cholinergic and serotonergic function in animals might provide a model of global dementia and amnesia. Brain Research 111: 125 (2000).
Thus, evidence suggests that the dementing and amnesic effects of Alzheimer's disease may result from alterations or damage to a number of different neurotransmitter systems and neuronal pathways. Neurobiol. Aging 14:343 (1993); Trends Neurosci. 14:220 (1991); Neurotransmitters and neuropeptides In: Alzheimer's Disease, Katzman (ed.) 247-61 (1994). Neurobiol. Aging 10:593 (1987); and J. Neurosci. 14:6317 (1994). However, there exists a lack of complete understanding of the varied neurotransmitter system and behavioral impairments found in human Alzheimer patients. Semin. Neurosci., 2:101 (1990); Annal. Neurol. 29:41 (1991); Trends Neurosci. 14:220 (1991). Additionally, the use of atypical antipsychotics to address the cognitive impairments of dementia (e.g., AD) has met with only limited success. Society of Biol. Psychiatry, 46:1243 (1999). Clearly, one problem with these strategies is that they ignore the influence of a multiplicity of lesions on the manifestation of these illnesses.
U.S. Pat. No. 4,624,852 is directed toward compositions useful for treating neurological disorders and aging. The compositions include: (a) choline or a choline precursor and (b) an amino acid which is a precursor to a neurotransmitter. The choline or choline precursor and amino acid are administered to a patient concomitantly. See, col. 2, lines 14-28. The choline or choline precursor and amino acid are co-administered to provide a synergistic result for the two components. See, Abstract. The choline can be administered as choline salts or esters. See, col. 2, lines 46-47. The specific esters disclosed therein include chloride bitartrate or stearate or the like, or as a compound that dissociates to choline, such as sphingomyelin, cytidine-diphospho-choline, an acylglycerophosphocholine, e.g., lecithin, lysolecithin, glycerophosphatidyl choline, mixtures thereof or the like. See, col. 2, lines 46-54.
Rispoli, et al., Neuroscience Letters, 356:199 (2004) is directed toward the use of choline pivaloyl esters to improve cognitive and memory performances. The two choline pivaloyl esters disclosed therein are: [2-(2,2-dimethylpropionyloxy)ethyl]trimethylammonium iodine and [2-(2,2-dimethylpropionyloxy)ethyl]trimetrhylammonium 2,2-dimethylpropionate. See, Abstract.
U.S. Pat. No. 4,963,556 is directed toward choline esters useful for drug absorption enhancing agents for drugs which are poorly absorbed from the nasal, oral, and vaginal cavities. See, Abstract. The choline esters are compounds of the formula:[(CH3)3N+CH2CH2OR]X−
wherein R is saturated acyl (C2-C20), acyl (C2-C20) with 1 to 6 double bonds, hydroxyacyl (C2-C20) with 1 to 3 hydroxy groups, ketoacyl (C4-C20), unsaturated hydroxyacyl (C5-C20), alkylaryl (C7-C20) arylacyl (C7-C20), alkylaryl (C7-C20) or carbalkoxyacyl (C5-C20) and X is a pharmaceutically acceptable counterion. See, claim 1. There is no disclosure or suggestion in the '556 patent that the choline esters described therein will have any therapeutic activity (e.g., useful in treating Alzheimer's disease).
U.S. Pat. No. 4,647,580 is directed toward tertiary amines useful for treating senile dementia of the Alzheimer's type. The tertiary amines are shown below:
wherein,
R1 is alkyl, alkoxy, alkylthio or dialkylamino hydroxyl, hydrogen, chlorine or fluorine; R2 is hydrogen, or when R1 is hydrogen, alkyl, alkoxy, alkylthio, alkylthioamino, hydroxyl, chlorine or fluorine; R3 is 1 to 2 carbon alkyl; R4 is 1 to 3 carbon alkyl; R5 is an optionally branched 3 to 12 carbon alkylene; X is oxygen or ethylene dioxy; and R6 is optionally branched or cyclic carbon group having less than eight carbons. See, Abstract.
New therapeutic strategies must be designed to accommodate the diverse neurochemical deficits seen in the AD population by restoring the functional integrity of a number of affected systems.